Regulation of platelet-trophoblast interaction and placental thrombo-inflammation via CLEC-2 and Podoplanin

• Applicant: Dr. Shrey Kohli
• Subject Area: Toxicology, Laboratory Medicine
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 538935031

Gestational vascular diseases are a major cause of maternal, fetal and neonatal morbidity and mortality. Furthermore, these complications have a major impact on both maternal and fetal health later in life. However, efficient therapeutic approaches to prevent such pregnancy complications are missing. Altered hemostatic system and platelet-activation has been shown to convey pathological effects during pregnancy. Maternal and embryonic factors regulating the hemostatic system and in-depth mechanistic details are not well known. Platelet-mediated inflammatory mechanisms within the placenta contribute to thrombo-inflammatory gestational vascular complications (TIGVCs) such as preeclampsia (PE). We have shown that platelet-activation causes a PE-like phenotype independent of their role in blood clotting. Specifically, extracellular vesicles (EVs) activate platelets within the placenta resulting in purinergic signaling and inflammasome activation in trophoblast cells. The activated platelets accumulate specifically within the placenta and are in direct contact with trophoblast cells. The interaction between C-type lectin-like type II transmembrane receptor (CLEC-2; expressed by platelets) and podoplanin (PDPN; expressed by trophoblast cells but not vascular endothelial cells) is a potential mechanism promoting platelet activation and thrombo-inflammation. However, their contribution to trophoblast and therefore placental disease has not been studied. We aim to identify the relevance and the molecular mechanism of the platelet CLEC-2 - trophoblast PDPN interaction in successful placentation versus placental thrombo-inflammation within the current proposal. Based on preliminary data and previously published findings, we hypothesize that PDPN while inducing trophoblast dysfunction via thrombo-inflammation by interacting with primed platelets that enter the placenta, it also may regulate physiological effects via PDPN-signaling during placentation. Accordingly, we have the following aims: 1) Evaluating the relevance and molecular mechanisms of the CLEC-2-podoplanin interaction for thrombo-inflammation. 2) Evaluating physiological PDPN signaling in trophoblast cells. Answering these questions will provide new insights into the cross-talk between platelets and trophoblast cells which results in thrombo-inflammatory placental pathologies such as PE. This will enable us to dissect the double edge functions of PDPN in placentation and may reveal new therapeutic targets enabling inhibition of excessive platelet activation or the consequences thereof, while still allowing successful placentation in high-risk pregnancies.

• DFG Programme: Research Grants